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Alpha-Ketoisocaproic Acid Increases Phosphorylation of Intermediate Filament Proteins from Rat Cerebral Cortex by Mechanisms Involving Ca2+ and cAMP

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We have previously described that α-ketoisocaproic acid (KIC), the main metabolite accumulating in maple syrup urine disease (MSUD), increased the in vitro phosphorylation of cytoskeletal proteins in cerebral cortex of 17- and 21-day-old rats through NMDA glutamatergic receptors. In the present study we investigated the protein kinases involved in the effects of KIC on the phosphorylating system associated with the cytoskeletal fraction and provided an insight on the mechanisms involved in such effects. Results showed that 1 mM KIC increased the in vitro incorporation of 32P into intermediate filament (IF) proteins in slices of 21-day-old rats at shorter incubation times (5 min) than previously reported. Furthermore, this effect was prevented by 10 μM KN-93 and 10 μM H-89, indicating that KIC treatment increased Ca2+/calmodulin- (PKCaMII) and cAMP- (PKA) dependent protein kinases activities, respectively. Nifedipine (100 μM), a blocker of voltage-dependent calcium channels (VDCC), DL-AP5 (100 μM), a NMDA glutamate receptor antagonist and BAPTA-AM (50 μM), a potent intracellular Ca2+ chelator, were also able to prevent KIC-induced increase of in vitro phosphorylation of IF proteins. In addition, KIC treatment was able to significantly increase the intracellular cAMP levels. This data support the view that KIC increased the activity of the second messenger-dependent protein kinases PKCaMII and PKA through intracellular Ca2+ levels. Considering that hyperphosphorylation of cytoskeletal proteins is related to neurodegeneration it is presumed that the Ca2+-dependent hyperphosphorylation of IF proteins caused by KIC may be involved to the neuropathology of MSUD patients.

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  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600 anexo, 90035-003, Porto Alegre, RS, Brasil

    Cláudia Funchal, Ariane Zamoner, André Quincozes dos Santos, Samanta Oliveira Loureiro, Moacir Wajner & Regina Pessoa-Pureur

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  1. Cláudia Funchal
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Funchal, C., Zamoner, A., Santos, A.Q.d. et al. Alpha-Ketoisocaproic Acid Increases Phosphorylation of Intermediate Filament Proteins from Rat Cerebral Cortex by Mechanisms Involving Ca2+ and cAMP. Neurochem Res 30, 1139–1146 (2005). https://doi.org/10.1007/s11064-005-7709-3

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